The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome
Keywords: 
Chronic lymphocytic-leukemia
Multiple-myeloma
Molecular classification
Methylation landscape
Lymphoma
Expression
Genes
Hypermethylation
Differentiation
Hypomethylation
Issue Date: 
2020
OpenAIRE: 
ISSN: 
2662-1347
Citation: 
Duran-Ferrer, M.; Clot, G.; Nadeu, F.; et al. "The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome". Nature Cancer. 1 (11), 2020, 1066 - 1081
Abstract
We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive individual-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. We construct a DNA-methylation-based mitotic clock, called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in differential diagnosis and the prediction of clinical outcome. Martin-Subero and colleagues analyze DNA methylation patterns in B-cell tumors and their normal cells of origin, and develop epiCMIT, a methylation-based mitotic clock with prognostic relevance.

Files in This Item:
Thumbnail
File
pdf.pdf
Description
Size
3.54 MB
Format
Adobe PDF


Items in Dadun are protected by copyright, with all rights reserved, unless otherwise indicated.